Association of Frailty, Age, and Biological Sex With Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine–Induced Immunity in Older Adults

  1. Janna R Shapiro
  2. Ioannis Sitaras
  3. Han Sol Park
  4. Tihitina Y Aytenfisu
  5. Christopher Caputo
  6. Maggie Li
  7. John Lee
  8. Trevor S Johnston
  9. Huifen Li
  10. Camille Wouters
  11. Pricila Hauk
  12. Henning Jacobsen
  13. Yukang Li
  14. Engle Abrams
  15. Steve Yoon
  16. Andrew J Kocot
  17. Tianrui Yang
  18. Yushu Huang
  19. Steven M Cramer
  20. Michael J Betenbaugh
  21. Amanda K Debes
  22. Rosemary Morgan
  23. Aaron M Milstone
  24. Andrew H Karaba
  25. Andrew Pekosz
  26. Sean X Leng
  27. Sabra L Klein

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Abstract

Background

Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized.

Methods

Plasma samples were collected from older adults (aged 75–98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18–74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs).

Results

Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females.

Conclusions

Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

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  1. Version published to 10.1093/cid/ciac397
  2. ScreenIT

    SciScore for 10.1101/2022.03.11.22272269: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: For both cohorts, written, informed consent was obtained from all participants, and the study protocols were approved by the Johns Hopkins School of Medicine Institutional Review Board.
    IRB: For both cohorts, written, informed consent was obtained from all participants, and the study protocols were approved by the Johns Hopkins School of Medicine Institutional Review Board.
    Sex as a biological variableMixed-effects models included an interaction term between time and cohort and were repeated separately for males and females.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Due to low plasma volumes, these amples were not tested for ACE2-inhibition, and data are missing for antibody titration against antigens from VOC for some participants.
    ACE2-inhibition
    suggested: None
    antigens
    suggested: None
    Data were expressed as the log10-transformed concentration (μg/ml) of ACE2-inhibiting antibodies (ACE2iAb), which are equivalent to anti-S monoclonal antibodies.
    anti-S
    suggested: None
    Software and Algorithms
    SentencesResources
    Analyses were performed in Stata 15 (StataCorp).
    StataCorp
    suggested: (Stata, RRID:SCR_012763)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study had several strengths and limitations. Some of the sex-specific effects observed were differences among males that were absent among females, without statistical evidence of a sex difference (i.e., non-significant sex interaction terms) [45]. It is important to note that our findings were generated from post-hoc analyses that were not necessarily powered to investigate sex differences, and conclusions are limited by small samples sizes in certain sub-groups. Given the small sample sizes, it is not surprising that statistically significant sex differences were not consistently observed. Particularly for age-based analyses, however, the consistency of trends between assays and timepoints, coupled with statistically significant sex differences in the effect of aging at 3M_PD2, lend credibility to the conclusion that the effects of age on antiviral antibody responses are driven by males. Further supporting these findings are similar sex-specific effects of age observed following seasonal influenza vaccination in both younger and older adults [17, 46]. While it is important to not over-interpret ‘within-sex’ differences as ‘between-sex’ differences [47], there is considerable value in studying differences within males or feamles [48, 49]. This is particularly true given the uniqueness of the community-dwelling older adult cohort, which represent the ‘oldest’ old subset, and are distinct from the population of long-term care facility residents that has been the focus of m...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2022.03.11.22272269v1 on medRxiv